Heavier time investment early on is expected to translate into a faster, more streamlined approval process.

Drug developers and others with a stake in bringing new drugs and biologics to market will have a chance today to sound off on a fifth authorization of the Prescription Drug User Fee Act (PDUFA V) when FDA holds a day-long public hearing on the topic. Their comments are expected to shape FDA’s final recommendation on PDUFA V, which the agency will send to Congress in January 2012.

The companies aren’t expected to disagree too much with the framework hammered out earlier this year by FDA and the two groups that represent drug developers, the Biotechnology Industry Organization (BIO) and the Pharmaceutical Research and Manufacturers of America (PhRMA).

Perhaps the most important change, as noted on the Proposed PDUFA V Reauthorization Performance Goals and Procedures for Fiscal Years 2013 through 2017, is that drug industry groups and FDA agreed that companies seeking approval for new drugs and biologics, as well as new indications for drugs already on the market, must communicate more with the agency than required under the current PDUFA IV, which expires at the end of September 2012.

According to the Draft Commitment Letter signed by FDA, BIO, and PhRMA, PDUFA V pushes back the start of FDA’s clock for its first review cycle to after its 60-day administrative filing review period. Once the clock starts, however, FDA is committed to reviewing and acting on 90% of standard New Molecular Entity (NME), New Drug Application (NDA), and original Biologics License Applications (BLA) submissions within 10 months—12 months from the date of filing—and on 90% of priority NME, NDA, and original BLA submissions within six months, or eight months from date of filing.

A presubmission meeting at which “the applicant is strongly encouraged to discuss the planned content of the application.”

A new mid-cycle meeting to which FDA will call an applicant, generally within two weeks after the agency holds its own internal mid-cycle review meeting on an application.

A late-cycle meeting at which FDA’s review team will meet with an applicant to discuss the status of agency review of the application late in the review cycle.

“What the industry wants to avoid is this syndrome: you submit your application and you suffer this radio silence,” Nancy Bradish Myers, president/founder of Catalyst Healthcare Consulting, told GEN. “One of the things the regulatory people in the companies are really clamoring for is predictability. I think this series of meetings will really help the people who are running the actual submission understand where the agency is in reviewing their submission. It is very important.”

What regulatory executives within drug developers also want, Myers said, is the opportunity to address FDA concerns as soon as they arise, rather than be lulled into thinking all is well, only to be jolted by a complete response letter (CRL) detailing issues that had not come up before.

Increasing Transparency

Andrew Emmett, BIO’s managing director for science and regulatory affairs, told GEN the new review model was a critical component of PDUFA V that marks a paradigm shift for FDA by introducing a new level of transparency in scientific discourse during the course of agency review.

“The underlying principle behind many of these recommendations is, frankly, that the scientific method doesn’t operate in a vacuum. FDA is a science-based agency, and it’s important that there be engagement and transparent dialogue between scientists throughout this process, both during drug development and during the actual review itself,” Emmett said. “If FDA and the sponsor are speaking, they can identify and mitigate any of these potential review issues during the first review cycle, and therefore lead to, hopefully, a first-cycle approval, and earlier patient access to novel therapies.”

If an application will be discussed at an Advisory Committee (AC) meeting, the late-cycle meeting will occur not less than 12 calendar days before the date of the AC meeting. AC meetings are set for no later than three months (under a standard review) or no later than two months (under a priority review) prior to the PDUFA goal date.

“Potential topics for discussion at the late-cycle meeting include major deficiencies identified to date; issues to be discussed at the AC meeting (if planned); current assessment of the need for risk evaluation management strategies [REMS] or other risk management actions; information requests from the review team to the applicant; and additional data or analyses the applicant may wish to submit.”

Drug developers agreed to the series of meetings with the expectation of a return on investment for all that time spent with regulators—namely a smoother ride to approval of their new medicines within a single cycle of review.

Meticulous Review vs. Faster Patient Access

Indeed the review model laid out by PDUFA V is intended to address a steady complaint of drug developers in recent years—that in the name of safety, FDA’s insistence on avoiding another Vioxx (the painkiller pulled from the market following its approval after patient claims linking it to heart attacks and strokes) has slowed down reviews of new treatments to a near standstill, posing a different sort of safety risk to patients.

There are signs that the proverbial pendulum has swung back in favor of drug developers. During the first half of 2011, FDA approved 20 new drugs, just one less than the number for all of 2010. And FDA has cited a study in Health Affairs showing that FDA reached approval decisions faster than the European Medicines Agency (EMA) on 35 cancer drugs approved by at least one of the agencies between October 2003 and December 2010—32 approvals in 261 days for FDA; 26 approvals in 373 days for EMA.

While FDA has maintained goals since 1997 of reviewing standard drug applications within 10 months, and priority applications within six, the agency acknowledges it has had difficulty meeting those timeframes. This has been especially the case since enactment of the Food and Drug Administration Amendments Act (FDAAA) of 2007, which allowed FDA to require post-marketing studies and clinical trials to address drug safety questions the agency deems unanswered to its satisfaction.

FDAAA lowered the percentage of new drugs, biologics, and efficacy supplements approved by FDA to below 80% in Q2 2009. By the first quarter of this year that percentage climbed back into the mid 90% range, about the same as in Q1 2005. The number of applications pending before FDA spiked up from 2,247 in October 2010 to 2,478 in June. But when only applications not blocked by patent issues are counted, the number dipped during that timeframe from 856 to 722.

Even though most applications get approved, they don’t all clear the first cycle. In July testimony to the House Energy and Commerce Committee, Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, said average first-cycle approval rate for standard NMEs have increased from an average of 30% in 1992 to 38% this year. That’s better than it could have been, but still disappointing, especially when the average cost of developing a drug and getting it through testing stood at an all-time high of $1.3 billion as of January. Priority NMEs have fared better with FDA, Woodcock testified, with approvals rising from 46% to 68%.

“I think we owe it to patients to do better than that. And that’s really why this new review model seeks to enhance the first cycle approval rate, so we can get to a first cycle approval at 8 or 12 months, rather than waiting 11 or 12, or 14 or 15 months,” Emmett said.

Mid-Cycle Meetings

Ensuring that applications clear the first cycle explains why the new mandatory mid-cycle meeting is especially significant. When industry representatives first proposed the idea last year, FDA balked at committing to discuss substantive issues and concerns with applicants at a formal meeting during the application review cycle.

“FDA stated that application review is only partially complete at mid-cycle, and comprehensive feedback would not be feasible at that stage,” the agency told industry representatives, according to the minutes of the FDA-Industry PDUFA V reauthorization meeting held Sept. 13, 2010. “While acknowledging the potential benefit of providing early feedback to sponsors, FDA stated that such mid-cycle feedback would also generate submission of further sponsor questions, requests for meetings, and submissions of application amendments that significantly increase the review workload as the reviewers attempt to stay on their originally-planned schedule.”

An explanation for FDA’s change of view was unavailable; a spokeswoman had not responded at deadline to that and other questions submitted to the agency.

FDA’s existing Good Review Management Principles and Practices for PDUFA Products guidance, issued in 2005, includes a nonbinding recommendation that the agency hold mid-cycle meetings where officials discuss progress and findings of reviews, consults, and inspections. Officials determine if any additional interaction with applicants is needed related to labeling, REMS, and postmarketing commitments.

“What’s missing is then a discussion with the sponsor about what issues have been identified, and how to resolve those issues. Typically, FDA will hold on to the issue until they issue a CRL several months later, and the sponsor doesn’t have an opportunity to help resolve it, even if it’s a minor issue—for example, pointing to something that’s already in the application, or conducting a minor fiscal re-analysis,” Emmett said.

Myers said the mid-cycle meetings are very important to drug or biologics applicants: “Who wants to be the head of regulatory affairs who gets that surprise complete response letter, and you have to go back and explain to your executive team and your investors why all of a sudden, something you thought was on track isn’t on track?”

Extra Funding

In addition to offering something for drug developers, PDUFA also gives FDA something it wanted—another $100 million to be collected from industry toward hiring staff to review drug and biologics applications. That raises to $3 billion the amount of user fees to be collected by the agency during PDUFA V, from $2.9 billion on hand for PDUFA IV.

Some of that funding will be used to address FDA priorities. By Sept. 30, 2013, the agency plans to develop a dedicated drug development communication and training staff within the Office of New Drugs in CDER, and increase the existing manufacturers’ assistance staff at FDA’s Center for Biologics Evaluation and Research, with the goal of enhancing communication between FDA and sponsors. Also by that date, FDA plans to hold a public meeting to discuss biomarkers and pharmacogenomics, and potential strategies to facilitate scientific exchanges within and outside of agency reviews. PDUFA V commits FDA to developing staff capacity to review submissions that involve pharmacogenomics and biomarkers.

“What we’ve discovered is that FDA has not always had the manpower, adequate fiscal staff, to review all of these submissions with biomarkers that are associated with them. It is important for FDA to be able to qualify new biomarkers for their use in a regulatory setting—both biomarkers developed through consortiums, and those that are unique to individual drug development programs,” Emmett said.

By Sept. 30, 2014, the OND drug development and communication staff will provide training to all CDER staff involved in review of INDs. And by March 31, 2015, FDA will publish draft guidance for review staff and industry describing best practices for communication between FDA and IND sponsors during drug development.

Orphan Drugs

Another significant portion of PDUFA V calls for beefing up staff focused on rare disease drug reviews. By Sept. 30, 2013, FDA committed itself to completing a staffing and implementation plan for the CDER Rare Disease Program within the Office of New Drugs. The plan calls for FDA to add five staffers to the CDER Rare Disease Program, and establish and fill a rare disease liaison position within CBER.

“It certainly is appropriate to begin with five. How many we will ultimately need, what’s the right number, I cannot say right now. But I do know when is the right time to start, and the answer is as soon as possible,” Timothy R. Coté, M.D., who until May headed FDA’s Office of Orphan Products Development, told GEN. He is now chief medical officer for the National Organization for Rare Disorders (NORD) and a faculty member at the Keck Graduate Institute.

According to Dr. Coté, the Office of Orphan Products Development had 38 FTEs when he left FDA, but the staff was dedicated to implementing the Orphan Drug Act, including its grants program and designation process.

Small as it may be, any help FDA can give to its rare disease drug development effort is especially welcome. But industry willingness to fund those jobs is less a matter of altruism than of emerging reality: These days, even big biopharma is interested in developing new drugs for orphan diseases affecting fewer than 200,000 people (U.S.) or fewer than 5 in 10,000 people (EU). As big biopharma struggles with the loss of patents for blockbusters, and with meager results for the billions spent on R&D over decades, it has finally embraced orphan drugs.

Likewise, the biopharma industry’s willingness to step up PDUFA funding overall shows how eager it is to shorten review timeframes and bring new drugs to market, even if it has to pay some more money and spend some more time in meetings to do so.

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